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Cell. 2018 Nov 1;175(4):1045-1058.e16. doi: 10.1016/j.cell.2018.10.037.

Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design.

Author information

1
Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK.
2
Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK.
3
Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK; School of Chemistry and Chemical Engineering, Queen's University, Belfast, UK.
4
Department of Molecular Microbiology, John Innes Centre, Norwich, NR4 7UH, UK.
5
Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
6
Department of Chemistry, Oxford, OX1 3QZ, UK.
7
Neurosciences Group, Nuffield Department of Clinical Neuroscience, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
8
Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK. Electronic address: Ben.Davis@chem.ox.ac.uk.
9
Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK. Electronic address: liz.carpenter@sgc.ox.ac.uk.

Abstract

Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (thus causing disease) and allow design of non-toxic "lipid-altered" tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed the design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo, providing a promising new class of antimicrobial drug.

KEYWORDS:

DPAGT1; GPT; Protein N-glycosylation; congenital disorders of glycosylation; congenital myasthenic syndrome; tunicamycin

PMID:
30388443
PMCID:
PMC6218659
DOI:
10.1016/j.cell.2018.10.037
[Indexed for MEDLINE]
Free PMC Article

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